Substituted piperazine derivatives, the preparation thereof and their use as medicaments

ABSTRACT

The present invention relates to substituted piperazine derivatives of general formula                    
     wherein 
     R a , R b , R c  R f , R g  and m, n and X are defined as in claim 1, the isomers and salts thereof, particularly the physiologically acceptable salts thereof, which are valuable inhibitors of the microsomal triglyseride-transfer protein (MTP), medicaments containing these compounds and their use, as well as the preparation thereof.

This application claims priority PCT/EP00/09146 and is a national stagecase filed under 35 USC 371.

The present invention relates to substituted piperazine derivatives ofgeneral formula

their isomers, their salts, particularly the physiologically acceptablesalts thereof which have valuable pharmacological properties.

The compounds of the above general formula I are valuable inhibitors ofthe microsomal triglyceride-transfer protein (MTP) and are thereforesuitable for lowering the plasma level of the atherogenic lipoproteins.

In the above general formula I

n denotes the number 1, 2, 3, 4 or 5,

m denotes the number 2 or 3,

X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene,imino or N-(C₁₋₃-alkyl)-imino group,

R_(a) denotes a phenyl group or heteroaryl group substituted by thegroups R₁ and R₂, wherein

R₁ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkylgroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, a hydroxy group, a C₁₋₄-alkoxy group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, aphenoxy, heteroaryloxy, phenyl-C₁₋₃-alkoxy, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,N,N-di-(C₁₋₃-alkyl)-aminocarbonyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkyl-amino,N-(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino, C₁₋₃-alkylcarbonylamino,N-(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonyl-amino, C₁₋₃-alkylsulphonyl-amino orN-(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group, while the abovementionedphenyl or heteroaryl moieties of the group R₁ may be substituted by oneto five fluorine, chlorine or bromine atoms, a C₁₋₃-alkyl group whereinthe hydrogen atoms may be wholly or partly replaced by fluorine atoms, ahydroxy group, or a C₁₋₄-alkoxy group wherein the hydrogen atoms may bewholly or partly replaced by fluorine atoms, and

R₂ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkylgroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, or a C₁₋₄-alkoxy group wherein the hydrogen atoms may bewholly or partly replaced by fluorine atoms, or

R₁ and R₂ together represent a methylenedioxy group, or R_(a) denotes amonocyclic heteroaryl or phenyl group which is substituted in each caseby a phenyl or monocyclic heteroaryl group, while the abovementionedphenyl groups and heteroaryl groups may in each case be substituted by afluorine, chlorine or bromine atom, a C₁₋₃-alkyl group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, by ahydroxy, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl, amino-carbonyl,C₁₋₃-alkylaminocarbonyl or N,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,

R_(b) and R_(c) independently of one another denote a hydrogen atom or aC₁₋₃-alkyl group and

R_(f) and R_(g), which may be identical or different, denote hydrogenatoms, C₁₋₆-alkyl groups wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, C₃₋₇-cycloalkyl groups, phenyl,heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl groups, while theabovementioned phenyl groups and heteroaryl groups may in each case besubstituted by one to three fluorine, chlorine or bromine atoms, by oneto three C₁₋₃-alkyl groups wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, by one to three hydroxy groups, oneto three C₁₋₃-alkoxy groups wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, or by a carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl,N,N-di-(C₁₋₃-alkyl)-aminocarbonyl, N,N-di-(C₁₋₃-alkyl)-amino, nitro oramino group, or

R_(f) and R_(g) together with the nitrogen atom between them denote a 3-to 7-membered cycloalkyleneimino group, while the methylene group in the4 position of a 6- or 7-membered cycloalkyleneimino group mayadditionally be replaced by an oxygen or sulphur atom, by a sulphinyl,sulphonyl, imino or N-(C₁₋₃-alkyl)-imino group,

while the tricyclic group in the abovementioned general formula I may bemono- or disubstituted by fluorine or chlorine atoms, by methyl ormethoxy groups and the substituents may be identical or different.

By the abovementioned heteroaryl groups are meant 6-membered heteroarylgroups containing one, two or three nitrogen atoms, or 5-memberedheteroaryl groups which may contain one to four heteroatoms such as, forexample, nitrogen, oxygen and sulphur, while hydrogen atoms bound tonitrogen may optionally be replaced by C₁₋₃-alkyl groups.

Preferred compounds of the above general formula I are those wherein

n denotes the number 3, 4 or 5,

m denotes the number 2 or 3,

X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene,imino or N-(C₁₋₃-alkyl)-imino group,

R_(a) denotes a phenyl group or heteroaryl group substituted by thegroups R₁ and R₂, wherein

R₁ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkylgroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, a hydroxy group, a C₁₋₄-alkoxy group wherein thehydrogen atoms may be wholly or partly replaced by fluorine atoms, aphenoxy, heteroaryloxy, phenyl-C₁₋₃-alkoxy, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,N,N-di-(C₁₋₃-alkyl)-aminocarbonyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkyl-amino,N-(C₁₋₃-alkyl)-phenyl-C₁₋₃-alkylamino, C₁₋₃-alkylcarbonylamino,N-(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkylsulphonylamino orN-(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group, while the abovementionedphenyl or heteroaryl moieties of the group R₁ may be substituted by oneto five fluorine, chlorine or bromine atoms, a C₁₋₃-alkyl group whereinthe hydrogen atoms may be wholly or partly replaced by fluorine atoms, ahydroxy group, or a C₁₋₄-alkoxy group wherein the hydrogen atoms may bewholly or partly replaced by fluorine atoms, and

R₂ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkylgroup wherein the hydrogen atoms may be wholly or partly replaced byfluorine atoms, or a C₁₋₄-alkoxy group wherein the hydrogen atoms may bewholly or partly replaced by fluorine atoms, or

R₁ and R₂ together represent a methylenedioxy group,

or R_(a) denotes a monocyclic heteroaryl or phenyl group which issubstituted in each case by a phenyl or monocyclic heteroaryl group,while the abovementioned phenyl groups and heteroaryl groups may in eachcase be substituted by a fluorine, chlorine or bromine atom, aC₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, by a hydroxy, or C₁₋₃-alkoxy group,

R_(b) and R_(c) independently of one another denote a hydrogen atom or aC₁₋₃-alkyl group and

R_(f) and R_(g), which may be identical or different, denote hydrogenatoms, C₁₋₆-alkyl groups wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, C₃₋₇-cycloalkyl groups, phenyl,heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl groups, while theabovementioned phenyl groups and heteroaryl groups may in each case besubstituted by one to three fluorine, chlorine or bromine atoms, by oneto three C₁₋₃-alkyl-groups, wherein the-hydrogen-atoms may be wholly orpartly replaced by fluorine atoms, by one to three hydroxy groups, oneto three C₁₋₃-alkoxy groups wherein the hydrogen atoms may be wholly orpartly replaced by fluorine atoms, or by a carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl,N,N-di-(C₁₋₃-alkyl)-aminocarbonyl, N,N-di-(C₁₋₃-alkyl)-amino, nitro oramino group, or

R_(f) and R_(g) together with the nitrogen atom between them denote a 3-to 7-membered cycloalkyleneimino group, while the methylene group in the4 position of a 6- or 7-membered cycloalkyleneimino group mayadditionally be replaced by an oxygen or sulphur atom, by a sulphinyl,sulphonyl, imino or N-(C₁₋₃-alkyl)-imino group,

the isomers and the salts thereof.

Particularly preferred compounds of the above general formula I arethose wherein

n denotes the number 3, 4 or 5,

m denotes the number 2 or 3,

X denotes a carbon-carbon bond or an oxygen atom,

R_(a) is as hereinbefore defined, and

R_(b) and R_(c) independently of one another denote a hydrogen atom or amethyl group and

R_(f) denotes a hydrogen atom, a C₁₋₆-alkyl group wherein thehydrogen-atoms may be wholly or partly replaced by fluorine atoms, aC₃₋₇-cycloalkyl group, phenyl, heteroaryl, phenyl-C₁₋₃-alkyl orheteroaryl-C₁₋₃-alkyl group, while the abovementioned phenyl groups andheteroaryl groups may in each case be substituted by one to threefluorine, chlorine or bromine atoms, by one to three C₁₋₃-alkyl groupswherein the hydrogen atoms may be wholly or partly replaced by fluorineatoms, by one to three hydroxy groups, one to three C₁₋₃-alkoxy groupswherein the hydrogen atoms may be wholly or partly replaced by fluorineatoms, or by a nitro or amino group, and

R_(g) denotes a hydrogen atom,

the isomers and the salts thereof.

The following are mentioned as examples of particularly valuablecompounds:

(a)9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide and

(b)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide,

the isomers and the salts thereof.

According to the invention, the new compounds are obtained by methodsknown from the literature, for example by the following methods:

a. reacting a compound of general formula

wherein

R_(a), R_(b) and R_(c) are as hereinbefore defined, with a compound ofgeneral formula

wherein n, R_(f), R_(g) and the tricyclic system are as hereinbeforedefined and

Z₁ denotes a nucleofugic leaving group such as a halogen atom, e.g. achlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as methylenechloride, acetonitrile, tetrahydrofuran, toluene, acetone/water,dimethylformamide or dimethylsulphoxide, optionally in the presence of abase such as sodium hydride, potassium carbonate, potassiumtert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and100° C., preferably at temperatures between 10 and 60° C.

b. reacting a compound of general formula

wherein

the tricyclic system is as hereinbefore defined, with an amine ofgeneral formula

wherein

R_(f) and R_(g) are as hereinbefore defined, or with the reactivederivatives thereof.

The reaction is expediently carried out with a corresponding halide oranhydride of general formula IV in a solvent such as methylene chloride,chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane,benzene, toluene, acetonitrile or sulfolane, optionally in the presenceof an inorganic or organic base at temperatures between −20 and 200° C.,but preferably at temperatures between −10 and 160° C. It may also,however, be carried out with the free acid, optionally in the presenceof an acid-activating agent or a dehydrating agent, e.g. in the presenceof isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,hydrogen chloride, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydrbxybenzotriazole,N,N′-carbonyldiimidazole or N,N′-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, at temperatures between −20 and200° C., but preferably at temperatures between −10and 160° C.

If according to the invention a compound of general formula I isobtained which contains a nitro group, it may be converted by reductioninto a corresponding amino compound or

if a compound of general formula I is obtained wherein R_(f) denotes ahydrogen atom, it may be converted by alkylation into a correspondingcompound wherein R_(f) denotes a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group.

The subsequent reduction of a nitro group is expediently carried outhydrogenolytically, e.g. with hydrogen in the presence of a catalystsuch as platinum, palladium/charcoal or Raney nickel in a suitablesolvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran,dioxane, dimethylformamide or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid and at a hydrogen pressureof 1 to 7 bar, but preferably 1 to 5 bar, with metals such as iron, tinor zinc in the presence of an acid such as acetic acid or hydrochloricacid, with salts such as iron(II)sulphate, tin (II) chloride, sodiumsulphide, sodium hydrogen sulphite or sodium dithionite, or withhydrazine in the presence of Raney nickel at temperatures between 0 and100° C., but preferably at temperatures between 20 and 60° C.

The subsequent alkylation is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran, dioxane, dimethylsulphoxide or sulfolane withan alkylating agent such as a corresponding halide or sulphonic acidester, e.g. with methyl iodide, ethyl bromide, dimethylsulphate orbenzyl chloride, optionally in the presence of a tertiary organic baseor in the presence of an inorganic base, expediently at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 100° C.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, tert.butyl-dimethylsilyl, acetyl, benzoyl, methyl,ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,

a protecting group for a carboxyl group may be a trimethylsilyl, methyl,ethyl, tert.butyl, benzyl or tetrahydropyranyl group and

protecting groups for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C. However, a silyl group may alsobe cleaved using tetrabutylammonium fluoride as described hereinbefore.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleavedfor example hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at temperatures between 20 and 60°C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatingwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

Moreover, the compounds of general formula I obtained maybe resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by, the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malicacid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. Anoptically active alcohol may be, for example, (+) or (−)-mentholand an optically active acyl group in amides may be, for example, a (+)-or, (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I thus obtained contain anacidic group such as a carboxy group, they may subsequently, if desired,be converted into the salts thereof with inorganic or organic bases,particularly for pharmaceutical use into the physiologically acceptablesalts thereof. Suitable bases for this purpose include for examplesodium hydroxide, potassium hydroxide, arginine, cyclohexylamine,ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulae II to VI used as starting materialsare known from the literature in some cases or may be obtained bymethods known from the literature or are described in the Examples.

The compounds of general formula II are obtained, for example, byreacting a compound of general formula

wherein R_(b) and R_(c) are as hereinbefore defined, Z₂ denotes aprotecting group for an amino group, e.g. the tert.butoxycarbonyl orbenzyloxycarbonyl group, and R_(a)′ denotes, for example, a phenyl ormonocyclic heteroaryl group substituted by a bromine or iodine atom,with a, for example, trifluoromethyl-substituted monocyclic aryl orheteroaryl group which is additionally substituted by a boric acidgroup, in the presence of a catalyst such as palladium acetate, a basesuch as potassium tert.butoxide and a phase transfer catalyst such astetrabutylammonium iodide in a solvent such as water, DMF, toluene ormixtures thereof at temperatures of between 20 and 130° C. Theprotecting group is cleaved by methods known from the literature andleads to a compound of general formula II.

A compound of general formula III is obtained, for example, by reactinga corresponding disubstituted carboxylic acid with an α,ω-dihaloalkanein the presence of a strong base such as lithium diisopropylamide,sodium amide or sodium hydride and subsequently reacting the carboxylicacid with a corresponding amine.

As already mentioned hereinbefore, the compounds of general formula Iand the physiologically acceptable salts thereof have valuablepharmacological properties. In particular, they are valuable inhibitorsof the microsomal triglyceride-transfer protein (MTP) and are thereforesuitable for lowering the plasma levels of the atherogenic lipoproteins.

For example, the compounds according to the invention were investigatedfor their biological effects as follows:

Inhibitors of MTP were identified by a cell-free MTP activity kit.Solubilised liver microsomes from various species (e.g. rat, pig) couldbe used as the MTP source. To prepare donor and acceptor vesicles,lipids dissolved in organic solvents were mixed in suitable proportionsand applied in a thin layer to the wall of a glass container by blowingthe solvent in a nitrogen current. The solution used to prepare donorvesicles contained 400 μM phosphatidylcholine, 75 μM cardiolipin and 10μM [¹⁴C]-triolein (68.8 μCi/mg). To prepare acceptor vesicles, asolution of 1.2 mM phosphatidylcholine, 5 μM triolein and 15 μM[³H]-dipalmitoylphosphatidylcholine (108 mCi/mg) was used. Vesicles areformed by wetting the dried lipids with test buffer and then subjectingto ultrasound. Vesicle populations of uniform size were obtained by gelfiltration of the ultrasonicated lipids. The MTP activity test containsdonor vesicles, acceptor vesicles and the MTP source in test buffer.Substances were added from concentrated DMSO-containing stock solutions;the final concentration of DMSO in the test was 0.1%. The reaction wasstarted by the addition of MTP. After a suitable incubation period thetransfer process was stopped by the addition of 500 μl of a SOURCE 30Qanion exchanger suspension (Pharmacia Biotech). The mixture was shakenfor 5 minutes and the donor vesicles bound to the anion exchangermaterial were separated off by centrifuging. The radioactivity of [3H]and [14C] found in the supernatant was determined by liquidscintillation measurement and from this the recovery of the acceptorvesicles and the triglyceride transfer rate were calculated.

In view of the abovementioned biological properties the compounds ofgeneral formula I and the physiologically acceptable salts thereof areparticularly suitable for lowering the plasma concentration ofatherogenic apolipoprotein B (apoB)-containing lipoproteins such aschylomicrons and/or very low density lipoproteins (VLDL) as well as theresidues thereof such as low density lipoproteins (LDL) and/orlipoprotein(a) (Lp(a)), for treating hyperlipidaemias, for preventingand treating atherosclerosis and the clinical sequela thereof, and forpreventing and treating related disorders such as diabetes mellitus,adiposity and pancreatitis, oral administration being preferred.

The daily dose needed to achieve such an effect is between 0.5 and 500mg, expediently between 1 and 350 mg, but preferably between 5 and 200mg, in adults.

For this purpose, the compounds of formula I prepared according to theinvention, optionally combined with other active substances such asother lipid-lowering agents, for example HMG-CoA-reductase inhibitors,cholesterol biosynthesis inhibitors such as squalene synthase inhibitorsand squalene cyclase inhibitors, bile acid-binding resins, fibrates,cholesterol resorption inhibitors, niacin, probucol, CETP inhibitors andACAT inhibitors may be incorporated together with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The Examples that follow are intended to illustrate the invention:

EXAMPLE 1 9-[4-(4-phenyl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoro-ethyl)-amide

a. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid

89 ml (0.11 mol) of a 1.6 M butyllithium solution in hexane are addeddropwise at 0° C. to a solution of 21 g (0.1 mol) of9-fluorenecarboxylic acid in 700 ml tetrahydrofuran under nitrogen andstirred for one hour. Then, still at 0° C., 13.13 ml (0.11 mol) ofdibromobutane are added and the solution is stirred for 30 hours atambient temperature. After this time, 50 ml of water are added and themixture is stirred for 30 minutes. The solution is evaporated down,combined with water and extracted with 250 ml of diethyl ether. Theaqueous phase is acidified with 150 ml of 1N hydrochloric acid andextracted three times with 250 ml of dichloromethane. The combinedorganic phases are dried over sodium sulphate and the solvent isremoved.

Yield: 18.5 g (53.6% of theoretical),

Melting point: 123° C.

b. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride

23 g (0.067 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid aredissolved in 40 ml dichloromethane and combined with three drops ofdimethylformamide and 6.96 ml (0.081 mol) of oxalyl chloride, dissolvedin 10 ml dichloromethane, under nitrogen at 0° C. The mixture is stirredfor 3 hours at ambient temperature. Then the solvent is removed and thecrude product is further reacted without any more purification.

Yield: 24 g (99% of theoretical)

c. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acidchloride are added dropwise at 0° C. under nitrogen to a solution of9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml(0.188 mol) of triethylamine in 550 ml of dichloromethane and stirredfor 2 hours at ambient temperature. The reaction mixture is extractedtwice with water, 1N hydrochloric acid and sodium hydrogen carbonatesolution. The organic phase is dried over sodium sulphate and thesolvent is distilled off. Purification is by column chromatography onsilica gel (eluant: cyclohexane/ethyl acetate=8:1).

Yield: 15.8 g (58.6% of theoretical),

Melting point: 172° C.

d. 9-[4-(4-phenyl-piperazin-1-yl)-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoro-ethyl)-amide

A suspension of 0.4 g (0.93 mmol) of9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide, 0.153 ml (1 mmol) of1-phenylpiperazine, 0.8 g of potassium carbonate and 1 ml water in 30 mldimethylformamide is stirred for 10 hours at 80° C. The reaction mixtureis then poured onto water, extracted with ethyl acetate and the organicphase is dried over sodium sulphate. Purification is by columnchromatography on silica gel (eluant: dichloromethane/methanol=15:1).

Yield: 0.1 g (19.7% of theoretical),

Melting point: 127-128° C.

EXAMPLE 29-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

a. 1-biphenyl-3-yl-piperazin-dihydrochloride

A suspension of 1 g (4.29 mmol) of 3-bromobiphenyl, 2.2 g (25.54 mmol)of piperazine and 2.499 g (26 mmol) of sodium tert.butoxide in 40 mltoluene is heated to 80 [sic] under nitrogen. Then 0.01 g (0.011 mmol)of tris(dibenzylidene-acetone)dipalladium(0) and 0.02 g (0.032 mmol) ofBINAP are added, the mixture is heated to 86 [sic] for 7 hours andstirred for 14 hours at ambient temperature. Water and ethyl acetate areadded in succession, theorganic phase is separated off, dried oversodium sulphate and evaporated down. The residue is combined with anethereal hydrochloric acid solution and diisopropyl ether and theprecipitate formed is filtered off.

Yield: 1.05 g (78.6% of theoretical),

Melting point: 219-221° C.

C₁₆H₁₈N₂ (M=238.34).

Calc.: molpeak (M+H)⁺: 239. Found: molpeak (M+H)⁺: 239.

b. 9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

A suspension of 0.2 g (0.643 mmol) of1-biphenyl-3-yl-piperazine-dihydrochloride, 0.256 g (0.6 mmol) of9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide and 0.1 g potassium carbonate in 20 mlof acetonitrile and 0.1 ml of water is stirred for 24 hours at 60° C.The reaction mixture is poured onto water, extracted with ethyl acetateand dried over sodium sulphate. Purification is by column chromatographyon silica gel (eluant: dichloromethane/ethanol=30:1).

Yield: 0.2 g (53.3% of theoretical),

C₃₆H₃₆F₃N₃O (M=583.70).

Calc.: molpeak (M)⁺: 583. Found: molpeak (M)⁺: 583.

EXAMPLE 39-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

a. 1-Benzyl-4-biphenyl-4-yl-piperazine

1.6 ml (0.05 mol) of butyllithium solution in n-hexane is added dropwiseto a solution of 8.81 g (0.05 mol) of 1-benzylpiperazine in 50 ml ofanhydrous THF under argon at 0° C. and stirred for one hour. Then 9.21 g(0.05 mol) of 4-methoxybiphenyl are added and the reaction mixture isrefluxed for 12 hours. The solvent is then evaporated off, the residueis combined with 150 ml of 2 N hydrochloric acid followed by diethylether and the precipitate formed is filtered off. The precipitate iswashed with diethyl ether, suspended in 20% sodium carbonate solutionand extracted several times with dichloromethane. After drying overmagnesium sulphate the solvent is removed and the residue is washed withethyl acetate and diethyl ether.

Yield: 12.5 g (85% of theoretical).

Melting point: 146-148° C.

b. 1-biphenyl-4-yl-piperazine

A suspension of 12.45 g (0.037 mol) of1-benzyl-4-biphenyl-4-yl-piperazine and 4 g of palladium hydroxide in360 ml of methanol is stirred for 6 hours at ambient temperature in aParr apparatus under a hydrogen pressure of 50 psi. The catalyst isseparated off and the filtrate is evaporated down.

Yield: 8.64 g (95.6% of theoretical),

Melting point: 134-138° C.

c. 9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

A solution of 0.4 g (1.678 mmol) of 1-biphenyl-4-yl-piperazine, 0.682 g(1.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide and 0.223 ml (1.6 mmol) oftriethylaminein 20 ml acetonitrile is stirred for 14 hours at 60° C. andthen diluted with water. It is extracted with ethyl acetate and theorganic phase is dried over sodium sulphate. Purification is by columnchromatography on silica gel (eluant: dichloromethane/ethanol=40:1).

Yield: 0.29 g (29.6% of theoretical),

Melting point: 209-211° C.

C₃₆H₃₆F₃N₃O (M=583.70).

Calc.: molpeak (M)⁺: 583. Found: molpeak (M)⁺: 583.

EXAMPLE 49-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(4-chloro-phenyl)-piperazinedihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.2 g (54.3% of theoretical),

Melting point: 166° C.

C₃₀H₃₁ClF₃N₃O (M=542.049).

Calc.: molpeak (M)⁺: 541/543. Found: molpeak (M)⁺: 541/543.

EXAMPLE 59-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(3-chlorophenyl)-piperazinedihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.09 g (16.5% of theoretical),

Melting point: 122° C.

C₃₀H₃₁ClF₃N₃O (M=542.049).

Calc.: molpeak (M+H)⁺: 542/544. Found: molpeak (M+H)⁺: 542/544.

EXAMPLE 69-{4-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(4-benzyloxy-phenyl)-piperazine hydrochloride and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.21 g (48.6% of theoretical),

Melting point: 180° C.

C₃₇H₃₈F₃N₃O₂ (M=613.73).

Calc.: molpeak (M+H)⁺: 614. Found: molpeak (M+H)⁺: 614.

EXAMPLE 79-{4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(4-trifluoromethyl-phenyl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.23 g (48.7% of theoretical).

Melting point: 176° C.

C₃₁H₃₁F₆N₃O (M=575.60)

Calc.: molpeak (M+H)⁺: 576. Found: molpeak (M+H)⁺: 576.

EXAMPLE 89-{4-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(3-trifluoromethyl-phenyl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.16 g (33.9% of theoretical),

C₃₁H₃₁F₆N₃O (M=575.60).

Calc.: molpeak (M+H)⁺: 576. Found: molpeak (M+H)⁺: 576.

EXAMPLE 99-{4-[4-(4-Fluorophenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(4-fluorophenyl)-piperazineand 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.1 g (23.2% of theoretical).

Melting point: 116-117° C.

C₃₀H₃₁F₄N₃O (M=525.59).

Calc.: molpeak (M+H)⁺: 526. Found: molpeak (M+H)⁺: 526.

EXAMPLE 109-{4-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.13 g (26% of theoretical).

Melting point: 96° C.

C₃₁H₃₀ClF₆N₃O (M=610.04).

Calc.: molpeak (M+H)⁺: 608/610. Found: molpeak (M+H)⁺: 608/610.

EXAMPLE 119-{4-[4-(4-methyl-phenyl)-3-methyl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(4-methyl-phenyl)-3-methyl-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.17 g (38.7% of theoretical).

C₃₂H₃₆F₃N₃O (M=535.65).

Calc.: molpeak (M)⁺: 535. Found: molpeak (M)⁺: 535.

EXAMPLE 129-{4-[4-(3,4-dichlorophenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(3,4-dichlorophenyl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.15 g (31.7% of theoretical).

Melting point: 122° C.

C₃₀H₃₀Cl₂F₃N₃O (M=576.49).

Calc.: molpeak (M)⁺: 575/577/579. Found: molpeak (M)⁺: 575/577/579.

EXAMPLE 139-{4-[4-(4-methoxy-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(4-methoxy-phenyl)-piperazineand 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.2 g (52.8% of theoretical).

Melting point: 120° C.

C₃₁H₃₄F₃N₃O₂ (M=537.63).

Calc.: molpeak (M+H)⁺: 538. Found: molpeak (M+H)⁺: 538.

EXAMPLE 149-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(2-methoxy-phenyl)-piperazineand 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.1 g (18.6% of theoretical).

C₃₁H₃₄F₃N₃O₂ (M=537.63).

Calc.: molpeak (M+H)⁺: 538. Found: molpeak (M+H)⁺: 538.

EXAMPLE 159-{4-[4-(2,4-Dimethoxy-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(2,4-dimethoxy-phenyl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.15 g (37.5% of theoretical).

C₃₂H₃₆F₃N₃O₃ (M=567.65).

Calc.: molpeak (M+H)⁺: 568. Found: molpeak (M+H)⁺: 568.

EXAMPLE 169-{4-[4-(5-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(5-chloro-2-methoxy-phenyl)-piperazine hydrochloride and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.11 g (27.3% of theoretical).

C₃₁H₃₃ClF₃N₃O₂ (M=572.07).

Calc.: molpeak (M+H)⁺: 572/574. Found: molpeak (M+H)⁺: 572/574.

EXAMPLE 179-{4-[4-(4-nitro-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(4-nitro-phenyl)-piperazineand 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.35 g (38.6% of theoretical).

Melting point: 146° C.

C₃₀H₃₁F₃N₄O₃ (M=552.60).

Calc.: molpeak (M)⁺: 552. Found: molpeak (M)⁺: 552.

EXAMPLE 189-{4-[4-(4-amino-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide hydrochloride

A solution of 0.25 g (0.45 mmol) of9-{4-[4-(4-nitro-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide in a mixture of 20 ml of ethyl acetateand 10 ml of methanol is hydrogenated in the presence of 0.1 g ofpalladium on charcoal. Then the catalyst is filtered off, the solvent isdistilled off and the residue is dissolved in ethanol. After theaddition of ethanolic hydrochloric acid solution the solvent isdistilled off.

Yield: 0.15 g (59.4% of theoretical).

Melting point: >270° C.

C₃₀H₃₃F₃N₄O X HCl (M=559.08).

Calc.: molpeak (M+H)⁺: 523. Found: molpeak (M+H)⁺: 523.

EXAMPLE 199-{4-[4-(2-methyl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-(2-methyl-phenyl)-piperazineand 9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.21 g (57.2% of theoretical),

C₃₁H₃₄F₃N₃O (M=521.63).

Calc.: molpeak (M+H)⁺: 522. Found: molpeak (M+H)⁺: 522.

EXAMPLE 209-{4-[4-Pyridin-2-yl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 1-pyridin-2-yl-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.15 g (35.9% of theoretical).

Melting point: 123° C.

C₂₉H₃₁F₃N₄O (M=508.59).

Calc.: molpeak (M+H)⁺: 509. Found: molpeak (M+H)⁺: 509.

EXAMPLE 219-{4-[4-(6-metboxy-pyridin-2-yl)-piperazin-l-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.38 g (60.1% of theoretical).

Melting point: 131° C.

C₃₀H₃₃F₃N₄O₂ (M=538.61).

Calc.: molpeak (M-H): 537. Found: molpeak (M-H); 537.

EXAMPLE 229-{4-[4-(6-methoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-4-fluorobenzyl-amide

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.

Yield: 0.05 g (10% of theoretical).

C₃₅H₃₇FN₄O₂ (M=564.70).

Calc.: molpeak (M-H): 563. Found: molpeak (M-H): 563.

EXAMPLE 239-{4-[4-(6-methoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-4-methoxybenzyl-amide

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxybenzyl-amide.

Yield: 0.02 g (8% of theoretical).

C₃₆H₄₀N₄O₃ (M=576.74).

Calc.: molpeak (M+H)⁺: 577. Found: molpeak (M+H)⁺: 577.

EXAMPLE 249-{4-[4-(6-ethoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-ethoxy-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.03 g (8.5% of theoretical).

C₃₁H₃₅F₃N₄O₂ (M=552.64).

Calc.: molpeak.(M+H)⁺: 553. Found: molpeak (M+H)⁺: 553.

EXAMPLE 259-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-methyl-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.04 g (7.7% of theoretical).

Melting point: 85-87° C.

C₃₀H₃₃F₃N₄O (M=522.61).

Calc.: molpeak (M+H)⁺: 523. Found: molpeak (M+H)⁺: 523.

EXAMPLE 269-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-4-fluorobenzyl-amide

Prepared analogously to Example 2 b from1-(6-methyl-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.

Yield: 0.16 g (44% of theoretical).

Melting point: 96-97° C.

C₃₅H₃₇FN₄O (M=548.71).

Calc.: molpeak (M+H)⁺: 549. Found: molpeak (M+H)⁺: 549.

EXAMPLE 279-{4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.19 g (33% of theoretical).

Melting point: 147-149° C.

C₃₀H₃₀F₆N₄O (M=576.59).

Calc.: molpeak (M+H)⁺: 577. Found: molpeak (M+H)⁺: 577.

EXAMPLE 289-{4-[4-(6-phenyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

a. tert.butyl 4-(6-bromo-pyridin-2-yl)-piperazine-1-carboxylate

A solution of 4 g (16.88 mmol) of 2,6-dibromopyridine, 3.14 g (16.88mmol) of tert.butyl piperazine-1-carboxylate and 5.89 ml (33.77 mmol) ofN,N-diisopropylethylamine in 30 ml of n-butanol is refluxed for eighthours. The solvent is then distilled off. Purification is by columnchromatography on silica gel (eluant: cyclohexane/ethyl acetate=2:1).

Yield: 2.2 g (38.1% of theoretical).

Melting point: 95° C.

C₃₀H₃₀F₆N₄O (M=576.59).

Calc.: molpeak (M+H)⁺: 577. Found: molpeak (M+H)⁺: 577.

b. tert.butyl 4-(6-phenyl-pyridin-2-yl)-piperazine-1-carboxylate

A mixture of 2 g (5.84 mmol) of tert.butyl4-(6-bromo-pyridin-2-yl)-piperazine-1-carboxylate, 0.75 g (6.15 mmol) ofphenylboric acid, 2.66 g (17.52 mmol) of caesium fluoride, 0.045 g (0.15mmol) of 2-(di-t-butylphosphino)-biphenyl and 0.013 g (0.06 mmol) ofpalladium acetate in 20 ml of dioxane is stirred for six hours at 50° C.under nitrogen. Then it is diluted with water and the reaction mixtureis extracted with ethyl acetate. The organic phase is separated off anddried over sodium sulphate. Purification is by column chromatography onsilica gel (eluant: cyclohexane/ethyl acetate=4:1).

Yield: 0.7 g (35.3% of theoretical).

C₂₀H₂₅N₃O₂ (M=339.44).

Calc.: molpeak (M+Na)⁺: 362. Found: molpeak (M+Na)⁺: 362.

b. [sic] 1-(6-phenyl-pyridin-2-yl)-piperazine

A solution of 0.7 g (2.06 mmol) of tert.butyl4-(6-phenyl-pyridin-2-yl)-piperazine-1-carboxylate and 3 ml oftrifluoroacetic acid in 30 ml of dichloromethane is stirred for threehours at ambient temperature. The solvent is then distilled off, theresidue is combined with water and made basic with sodium hydroxidesolution. It is then extracted with dichloromethane and the organicphase is separated off and dried over sodium sulphate.

Yield: 0.4 g (81.1% of theoretical).

C₁₅H₁₇N₃ (M=239.32).

Calc.: molpeak (M+H)⁺: 240. Found: molpeak (M+H)⁺: 240.

d.9-{4-[4-(6-phenyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-phenyl-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.05 g (17.1% of theoretical).

Melting point: 63° C.

C₃₅H₃₅F₃N₄O (M=584.69).

Calc.: molpeak (M+H)⁺: 585. Found: molpeak (M+H)⁺: 585.

EXAMPLE 299-{4-[4-(4-phenyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(4-phenyl-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.11 g (26.7% of theoretical).

Melting point: 59° C.

C₃₅H₃₅F₃N₄O (M=584.69).

Calc.: molpeak (M+H)⁺: 585. Found: molpeak (M+H)⁺: 585.

EXAMPLE 309-{4-[4-(6-phenoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2i2-trifluoroethyl)-amide

a. 2-Chloro-6-phenoxy-pyridine

A reaction mixture consisting of 1.48 g (10 mmol) of2,6-dichloropyridine, 6 g (63.75 mmol) of phenol and 2.4 g (60 mmol) ofsodium hydroxide in 10 ml of water is heated to 140° C. for 24 hours ina bomb. After cooling the reaction mixture is made strongly alkalinewith sodium hydroxide solution and extracted with dichloromethane. Theorganic phase is separated off and dried over sodium sulphate.Purification is by column chromatography on silica gel (eluant:cyclohexane/ethyl acetate=3:1).

Yield: 0.3 g (14.6% of theoretical).

C₁₁H₈ClNO (M=205.64).

Calc.: molpeak (M+H)⁺: 205/207. Found: molpeak (M+H)⁺: 205/207.

b.9-{4-[4-(6-phenoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from 2-chloro-6-phenoxy-pyridine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.045 g (15.4% of theoretical).

C₃₅H₃₅F₃N₄O₂ (M=600.69).

Calc.: molpeak (M+H)⁺: 601. Found: molpeak (M+H)⁺: 601.

EXAMPLE 319-(4-{4-[6-(4-Chloro-phenoxy)-pyridin-2-yl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-[6-(4-chloro-phenoxy)-pyridin-2-yl]-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.04 g (15.1% of theoretical).

C₃₅H₃₄ClF₃N₄O₂ (M=635.13).

Calc.: molpeak (M+H)⁺: 635/637. Found: molpeak (M+H)⁺: 635/637.

EXAMPLE 329-(4-{4-[6-(3-Chloro-phenoxy)-pyridin-2-yl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-[6-(3-chloro-phenoxy)-pyridin-2-yl]-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.04 g (15.1% of theoretical).

C₃₅H₃₄C1F₃N₄O₂ (M=635.13).

Calc.: molpeak (M+H)⁺: 635/637. Found: molpeak (M+H)⁺: 635/637.

EXAMPLE 339-(4-{4-[6-(2-Chloro-phenoxy)-pyridin-2-yl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-[6-(2-chloro-phenoxy)-pyridin-2-yl]-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.06 g (22.7% of theoretical).

C₃₅H₃₄ClF₃N₄O₂ (M=635.13).

Calc.: molpeak (M)⁺: 634/636. Found: molpeak (M)⁺: 634/636.

EXAMPLE 349-(4-{4-[6-(4-methoxy-phenoxy)-pyridin-2-yl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-[6-(4-methoxy-phenoxy)-pyridin-2-yl]-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.03 g (11.2% of theoretical).

C₃₆H₃₇F₃N₄O₃ (M=630.71).

Calc.: molpeak (M+H)⁺: 631. Found: molpeak (M+H)⁺: 631.

EXAMPLE 359-{4-[4-(6-methoxy-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-xanthene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-piperazine and9-(4-bromo-butyl)-9H-xanthene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.17 g (45.2% of theoretical).

Melting point: 122° C.

C₃₀H₃₃F₃N₄O₃ (M=554.61).

Calc.: molpeak (M+H)⁺: 555. Found: molpeak (M+H)⁺: 555.

EXAMPLE 369-{4-[4-(6-methoxy-pyridin-2-yl)-2,6-dimethyl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.07 g (13.2 % of theoretical).

Melting point: 122° C.

C₃₂H₃₇F₃N₄O₂ (M=566.67).

Calc.: molpeak (M+H)⁺: 567. Found: molpeak (M+H)⁺: 567.

EXAMPLE 379-{4-[4-(6-methoxy-pyridin-2-yl)-2,6-dimethyl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-4-fluorobenzyl-amide.

Prepared analogously to Example 2 b from1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.

Yield: 0.16 g (40.7% of theoretical).

Melting point: 78-79° C.

C₃₇H₄₁FN₄O₂ (M=592.76).

Calc.: molpeak (M-H): 591. Found: molpeak (M-H): 591.

EXAMPLE 389-{4-[4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

Prepared analogously to Example 2 b from1-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine and9-(4-bromo-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide.

Yield: 0.05 g (23.4% of theoretical).

Melting point: 115° C.

C₃₂H₃₂F₃N₅OS (M=591.70).

Calc: C: 64.95 H: 5.46 N: 11.84 S: 5.42 F: 9.63 Found: C: 64.92 H: 5.73N: 11.50 S: 5.70 F: 9.28

The following compounds may be prepared analogously to Examples 1 to 38:

(1)9-{4-[4-(4′-fluoro-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(2)9-{4-[4-(3′-fluoro-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(3)9-{4-[4-(2′-fluoro-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(4)9-{4-[4-(4′-chlorobiphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(5)9-{4-[4-(3′-chlorobiphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(6)9-{4-[4-(2′-chlorobiphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(7)9-{4-[4-(4′-trifluoromethyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(8)9-{4-[4-(3′-trifluoromethyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide (9)9-{4-[4-(2′-trifluoromethyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(10)9-{4-[4-(4′-methyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(11)9-{4-[4-(3′-methyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(12)9-{4-[4-(2′-methyl-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(13)9-{4-[4-(4′-methoxy-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(14)9-{4-[4-(3′-methoxy-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(15)9-{4-[4-(2′-methoxy-biphenyl-4-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(16)9-{4-[4-(4′-fluoro-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(17)9-{4-[4-(3′-fluoro-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(18)9-{4-[4-(2′-fluoro-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(19)9-{4-[4-(4′-chlorobiphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(20)9-{4-[4-(3′-chlorobiphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(21)9-{4-[4-(2′-chlorobiphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(22)9-{4-[4-(4′-trifluoromethyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(23)9-{4-[4-(3′-trifluoromethyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(24)9-{4-[4-(2′-trifluoromethyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(25)9-{4-[4-(4′-methyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(26)9-{4-[4-(3′-methyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(27)9-{4-[4-(2′-methyl-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(28)9-{4-[4-(4′-methoxy-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(29)9-{4-[4-(3′-methoxy-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(30)9-{4-[4-(2′-methoxy-biphenyl-3-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(31)9-{4-[4-(3-Thiazol-2-yl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(32)9-{4-[4-(3-Thiophen-3-yl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(33)9-(4-{4-[3-(1H-imidazol-4-yl)-phenyl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(34)9-(4-{4-[3-(1H-Pyrrol-2-yl)-phenyl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(35)9-{4-[4-(4-Thiazol-2-yl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid (2,2,2-trifluoroethyl)-amide

(36)9-{4-[4-(4-Thiophen-3-yl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(37)9-(4-{4-(4-(1H-imidazol-4-yl)-phenyl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(38)9-(4-{4-[4-(1H-Pyrrol-2-yl)-phenyl]-piperazin-1-yl}-butyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(39)9-{4-[4-(4-Pyridin-2-yl-phenyl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(40)9-{4-[4-(6-phenyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2, 2-trifluoroethyl)-amide

(41)9-{4-[4-(4-phenyl-pyrimidin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(42)9-{4-[4-(2-phenyl-pyrimidin-5-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid7 (2,2,2-trifluoroethyl)-amide

(43)9-{4-[4-(5-phenyl-pyridin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(44)9-{4-[4-(5-phenyl-thiophen-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(45)9-{4-[4-(5-phenyl-oxazol-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(46)9-[4-(4-[2,2′]Bipyridinyl-6-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(47)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-methylamide

(48)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-ethylamide

(49)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-propylamide

(50)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-isopropylamide

(51)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-benzylamide

(52)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-phenylamide

(53)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(pyridin-2-yl)-amide

(54)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(4-fluorophenyl)-amide

(55)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(3-chlorophenyl)-amide

(56)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-dimethylamide

(57)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-diethylamide

(58){9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-yl}-aziridin-1-yl-methanone

(59){9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-yl}-azetidin-1-yl-methanone

(60){9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-yl}-pyrrolidin-1-yl-methanone

(61){9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-yl}-piperidin-1-yl-methanone

(62){9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-yl}-morpholin-1-yl-methanone

(63)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-2-fluoro-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(64)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-2-methyl-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(65)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-2-chloro-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(66)9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-3-methoxy-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(67)9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-2-fluoro-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(68)9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-2-methyl-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(69)9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-2-chloro-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(70)9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-3-methoxy-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(71)9-[3-(4-biphenyl-4-yl-piperazin-1-yl)-propyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(72)9-[3-(4-biphenyl-3-yl-piperazin-1-yl)-propyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(73)9-{4-[4-(6-methoxy-pyridin-2-yl)-2-(R,S)-methyl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(74)9-{4-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-butyl}-9-H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

(75)9-(5-{4-[6-(pyridin-3-yloxy)-pyridin-2-yl]-piperazin-1-yl}-pentyl)-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide

EXAMPLE 40 Tablets Containing 5 mg of Active Substance Per Tablet

Composition:

active substance 5.0 mg lactose monohydrate 70.8 mg microcrystallinecellulose 40.0 mg sodium carboxymethylcellulose, insolubly crosslinked3.0 mg magnesium stearate 1.2 mg

Preparation:

The active substance is mixed for 15 minutes with lactose monohydrate,microcrystalline cellulose and sodium carboxymethylcellulose in asuitable diffusion mixer. Magnesium stearate is added and mixed with theother substances for another 3 minutes.

The finished mixture is compressed in a tablet press to form facettedflat round tablets.

Diameter of the tablet: 7 mm

Weight of a tablet: 120 mg

EXAMPLE 41 Capsules Containing 50 mg of Active Substance Per Capsule

Composition:

active substance 50.0 mg lactose monohydrate 130.0 mg corn starch 65.0mg highly dispersed silicon dioxide 2.5 mg magnesium stearate 2.5 mg

Preparation:

A starch paste is prepared by swelling some of the corn starch in asuitable amount of hot water. The paste is then left to cool to roomtemperature.

The active substance is premixed for 15 minutes in a suitable mixer withlactose monohydrate and corn starch. The starch paste is added and themixture is mixed with sufficient water to produce a moist homogeneousmass. The moist mass is passed through a screen with a mesh size of 1.6mm. The screened granules are dried on racks at about 55° C. for 12hours.

The dried granules are then passed through screens with mesh sizes of1.2 and 0.8 mm. Highly dispersed silica is mixed with the granules in asuitable mixer for 3 minutes. Then magnesium stearate is added andmixing is continued for another 3 minutes.

The finished mixture is packed into empty size 1 hard gelatine capsuleshells using a capsule filling machine.

EXAMPLE 42 Tablets Containing 200 mg of Active Substance Per Tablet

Composition:

active substance 200.0 mg lactose-monohydrate 167.0 mg microcrystallinecellulose 80.0 mg hydroxypropyl-methylcellulose, type 2910 10.0 mgpoly-1-vinyl-2-pyrrolidone, insolubly crosslinked 20.0 mg magnesiumstearate 3.0 mg

Preparation:

HPMC is dispersed in hot water. After cooling, the mixture yields aclear solution.

The active substance is premixed in a suitable mixer for 5 minutes withlactose monohydrate and microcrystalline cellulose. The HPMC solution isadded and the mixing is continued until a homogeneous moist compositionis obtained. The moist composition is passed through a screen with amesh size of 1.6 mm. The screened granules are dried on racks at about55° C. for 12 hours.

The dried granules are then passed through screens with mesh sizes of1.2 and 0.8 mm. Poly-1-vinyl-2-pyrrolidone is mixed with the granules ina suitable mixer for 3 minutes. Then magnesium stearate is added andmixing is continued for another 3 minutes.

The finished mixture is compressed in a tablet press to form oblongtablets (16.2×7.9 mm).

Weight of a tablet: 480 mg

What is claimed is:
 1. A compound of the formula (I)

wherein n denotes the number 1, 2, 3, 4 or 5, m denotes the number 2, Xdenotes a carbon-carbon bond, R_(a) denotes a phenyl group or aheteroaryl group chosen from pyridinyl, pyrimidinyl, thiophenyl,oxazolyl and 1, 2, 4 thiadiazolyl each substituted by the groups R₁ andR₂, wherein R₁ denotes a hydrogen, fluorine, chlorine, a C₁₋₃-alkylgroup wherein the hydrogen atoms of the alkyl are optionally wholly orpartly replaced by fluorine atoms, a C₁₋₄-alkoxy group, a phenoxy,phenyl-C₁₋₃-alkoxy, nitro or amino, wherein the abovementioned phenyl ofthe phenoxy is optionally substituted by chlorine or methoxy, and R₂denotes a hydrogen, chlorine or C₁₋₄-alkoxy, or R_(a) denotes aheteroaryl chosen from pyridinyl, pyrimidinyl thiophenyl, oxazolyl and1, 2, 4 thiadiazolyl or phenyl group which is substituted in each caseby a phenyl group, R_(b) and R_(c) independently of one another denote ahydrogen atom or a C₁₋₃-alkyl group and R_(f) denotes C₁₋₆-alkyl whereinthe hydrogen atoms of the alkyl are optionally wholly or partly replacedby fluorine atoms, phenyl-C₁₋₃-alkyl wherein the phenyl is optionallysubstituted by fluorine or C₁₋₃-alkoxy, R_(g) is hydrogen; or theenantiomeres, diastereomers or the salts thereof.
 2. The compoundaccording to claim 1, wherein n denotes the number 3, 4 or
 5. 3. Thecompound according to claim 1, wherein R_(b) and R_(c) independently ofone another denote a hydrogen atom or a methyl group.
 4. The compoundaccording to claim 1, wherein n denotes the number 4, m denotes thenumber
 2. 5. A compound chosen from9-[4-(4-biphenyl-3-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide and9-[4-(4-biphenyl-4-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylicacid-(2,2,2-trifluoroethyl)-amide or the enantiomeres, diastereomers orthe salts thereof.
 6. A physiologically acceptable salt of the compoundaccording to claim
 1. 7. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim 1with one or more pharmaceutically acceptable inert carriers and/ordiluents.
 8. A method of treating a disease selected fromhyperlipidaemias, atherosclerosis, diabetes mellitus, adiposity andpancreatitis, said method comprising administering to a patient in needthereof a pharmaceutically effective amount of a compound according toclaim
 1. 9. The method according to claim 8 wherein the compound iscombined with another lipid-lowering agent.
 10. Process for preparing acompound of the formula (I) according to claim 1, comprising a) reactingunder suitable conditions a compound of formula

wherein R_(a), R_(b) and R_(c) are defined as in claim 1, with acompound of formula

wherein n, R_(f), R_(g) and the tricyclic system are defined as in claim1 and Z₁ denotes a nucleofugic leaving group, or b) reacting undersuitable conditions a compound of formula

with an amine of formula

wherein R_(f) and R_(g) are defined as in claim 1, or with the reactivederivatives thereof and c) optionally reducing under suitable conditionsthe product of a) or b) which contains a nitro group if desired into acorresponding amino compound and/or d) if R_(f) denotes a hydrogen atomalkylating under suitable conditions the product into a correspondingcompound wherein R_(f) denotes a phenyl-C₁₋₃-alkyl group, and/or e)cleaving under suitable conditions any protecting group using to protectreactive groups during the reactions and/or resolving the product any ofthe product above into its stereoisomers and/or converting any of theproducts above into the physiologically acceptable salts thereof.